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Gout — new and emerging insights into an old disease

Gout is one of the oldest rheumatic diseases. In antiquity, descriptions of gout depicted a similar illness to what we see today, confirmed by studies of Egyptian mummies. It is now the most common form of inflammatory arthritis in adults, related in part to increasing age, rising prevalence of comorbidities and more widespread use of medications that raise uric acid levels.

Hippocrates described a crippling condition with tophi in the joints and described sufferers as being “beyond the power of medicine to cure”. As the holiday season ends, for those who have been able to celebrate traditional embellishments and libations with friends and family, gout may be a problem.

Until recent times, some medical professionals looked at gout as almost a ‘punishment’ meted out to those who indulged in life’s excesses. Myths and old adages about gout and its treatment persist to this day, but how true are they? In the following article I will discuss new insights into gout, a recently-proposed set of classification criteria by EULAR and ACR, and new therapies. In addition, studies exploring the link between uric acid and cardiovascular disease, and the benefits of a ‘treat-to-target’ management strategy, will be reviewed.

Gout is a systemic arthritis characterised by recurrent attacks of arthritis. In milder forms, sporadic attacks of monoarthritis or oligoarthritis occur at times of extreme changes in serum uric acid levels. In more aggressive disease, recurrent or chronic attacks lead to erosions, bursitis, tophaceous deposits and nephrolithiasis, causing significant disability. Today it is clear that many people who develop gout are neither wealthy over-indulgers nor alcoholics. Many risk factors have been clearly elucidated, including advancing age, multiple medical conditions and medications, some of which are listed in Table 1.


Table 1: Risk factors for gout identified from multiple studies

Although rare inherited disorders such as Lesch-Nyhan syndrome predispose to gout, much more commonly many patients have a strong family history, with one or more first-degree relatives affected.

There are three important features of the association between serum uric acid and clinical gout. Firstly, the higher the uric acid, the greater the risk of developing gout (Table 1). Secondly, gout cannot be diagnosed by measuring uric acid; approximately 10 per cent of gout patients will have normal uric acid, and exactly why some people with hyperuricaemia develop gout and others with similar levels do not remains unsolved.

New insights suggest interleukin-1 activity is a critical cytokine, but exactly why remains elusive. Once someone has gout diagnosed, serum uric acid measurement is a very important tool for monitoring response to therapy.

Other medications lower uric acid, including high-dose aspirin, losartan, fenofibrates and leflunomide. Thus a hypertensive patient with gout or at risk for gout may be better off, from a gout perspective at least, on losartan than a thiazide diuretic for blood pressure control; unnecessary aspirin use should be discouraged.

Finally, local environmental factors are likely important and a recent study has strongly linked the sugar (fructose) in US beverages to the higher rates of gout there than other countries which use different sugars in similar beverages. High uric acid is an important biomarker in other diseases such as renal disease, pre-eclampsia and HELLP syndrome, and cardiovascular disease where higher levels portend a worse outcome.

Attacks of gout can occur in any joint but the first MTP, ankle and knee appear to have a particular predilection for gout attacks. They are usually characterised by fairly sudden and dramatic onset of severe pain, redness and tenderness and may or may not be accompanied by fevers, cellulitis and soft-tissue swelling [Fig 1].


Figure 1: A typical attack may involve the first MTP and ankle

Attacks usually subside within days or one-to-two weeks, but occasionally last longer. Some patients have very little pain but chronic synovitis and erosive arthritis are more typical of rheumatoid or other inflammatory arthritis. While the spine is rarely affected, there are documented cases involving the spine, with erosions and tophaceous deposits rarely resulting in neurologic compromise.

Tophaceous deposits usually occur in the soft tissues, often close to the joint, but may occur in the elbow (Fig 2a) or pulps of the fingers (Fig 2b) or pinna of the ear.


Figure 2: Tophi can be present at the elbows or in the pulps of the fingers

Measuring uric acid levels is appropriate but may be misleading in an acute attack as the flares can result from a rapid increase or decrease in serum uric acid levels. Differential diagnosis includes other forms of inflammatory arthritis such as pseudo-gout, rheumatoid arthritis and other inflammatory arthritis, as well as infectious arthritis. Arthrocentesis and blood cultures are absolutely required if septic arthritis is a concern. Note: patients can have gout and sepsis simultaneously. (Fig 2)

Distinguishing one from the other on clinical grounds is not possible. FBC, chemistry panel, a C-reactive protein and perhaps other testing can be helpful. X-rays are not helpful during acute attacks unless another diagnosis is suspected.

Definite diagnosis of gout traditionally requires:

  1. Demonstration of negatively birefringent needle-shaped crystals on a specimen of joint fluid using a polarised microscope.
  2. Similar findings on a specimen of tophus.
  3. Demonstration of classical gouty erosions on imaging: juxta-articular with overhanging edge; a double-contour sign on ultrasound and dual-energy CT scans are gaining popularity.
  4. Stone analysis showing predominant content to be uric acid.

All others should be considered as having ‘probable’ gout or ‘possible’ gout. In reality, not all rheumatologists have access to a polarised microscope, nor the interest or training in crystal identification. And since all tests are imperfect, it is reasonable in clinical practice, where crystal identification is impractical or impossible, to diagnose gout in patients with recurrent attacks typical for gout, with hyperuricaemia without definite crystals.

In order to address this issue for clinical trials and studies of gout populations, the American College of Rheumatology and The European League Against Rheumatism recently presented the results of a new classification schema designed to classify patients based on their clinical presentation, serum uric acid, radiology finds and the presence of tophi.

Patients must score at least eight points on a 23-point scale to be classified as ‘gout’, if crystal identification is not possible or absent. Importantly, demonstration of tophi, typical erosions and the ‘double-contour’ sign each weigh-in heavily, with four points each. Nephrolithiasis was not part of these new classification criteria.

Importantly for clinicians, as with many ACR classification criteria, these should not be confused with diagnosis.

Once a diagnosis of gout has been established it is important to:

  1. Treat the acute attack if present.
  2. Address any lifestyle, medication, comorbidities, if relevant.
  3. Consider whether uric acid-lowering therapy (ULT) is required.

Treatment strategies for acute attacks follow a few general principles: rest, fluids, analgesia and anti-inflammatory medications.

In the case of the latter, the three main options are NSAIDs, corticosteroids and/or colchicine. The pros and cons of the various therapies are outlined in Table 2.


Table 2: Potential benefit and risk of various acute therapies

The decision to instigate ULT is not always an easy one. As a good rule of thumb, if the patient has two or more attacks per year, severe attacks, erosions, tophi and perhaps those with high uric acid and significant non-modifiable comorbidities should be considered as reasons to start ULT.

The target uric acid is best attained with a combination of lifestyle, medication and ULT management. A lot of attention has been given to ‘treat-to-target’ strategies in recent years in many fields, including rheumatology.

Gout probably is the ‘Holy Grail’ of such a strategy, as simply treating the uric acid to a value <300 will result in eventual quiescence and resolution of tophi, stones, and strikingly after many years, sometimes the erosions. Allopurinol is the preferred, tried and trusted option. The usual starting dose is 300mg per day, which can be titrated up at one-to-three monthly intervals.

The average drop in uric acid with a 300mg/day dose is 150 from clinical trials, noting considerable variability in individual patients. In patients with chronic renal insufficiency, a lower dose is often sufficient, starting with 100mg and titrating up in a similar manner. Generally, we recommend treating with low-dose colchicine 0.5mg once or twice daily for six-to-12 months, while initiating therapy and stopping this once the uric acid has been normal for six months and there have been no further flare-ups.

While NSAIDs and low-dose corticosteroids are recommended by some guidelines, this is not best practice since many of the patients with gout already have, or are at significant risk for, cardiovascular disease, renal disease and/or diabetes mellitus. Febuxostat is another option and is a potent ULT therapy. The available dose of 80mg is equivalent in price and efficacy to 600-800mg of allopurinol.

Note that in studies comparing febuxostat to a starting dose of allopurinol, there was a higher flare rate of gout in the first six months, so a gradual reduction over months is favoured, rather than a precipitous drop. Complex cases should be referred to a rheumatologist.

Newer, more expensive options are available for severe refractory gout including rasburicase and pegylated uricase. Interleukin-1 inhibition with anakinra may be an option as a daily injection, as its relative canakinumab, while effective, is very expensive. Analgesia is important; most patients manage with these therapies and a few days of paracetamol with codeine. Rarely, stronger analgesia is required or hospitalisation for severe attacks.

Unfortunately, studies show gout is badly managed by many physicians and surgeons, including rheumatologists. Many patients with severe erosive tophaceous gout continue to deteriorate with no dose escalation of therapy and have persistently elevated uric acid. Such patients can get severe infections or limb- or digit-threatening gout or require joint replacements.

Treatment is massively effective, is for life, and gout is possibly the most treatable disease in medicine

This should be the exception with our modern therapies, rather than the norm. All patients with such disease should be treated until an appropriate agreed uric acid target has been met. Treatment is massively effective, is for life, and gout is possibly the most treatable disease in medicine.

Stopping patients’ medication during an acute attack or hospitalisation is nonsense. All it does is increase the severity of the patients’ gout in the long-term and is an outdated adage without evidence.

Another myth is that ULT should not be started during an acute attack. Many proponents make a good case that this is the best time to start it, as you are treating the acute attack anyway. There are no high-quality, large studies to evaluate this strategy but it has been my practice for years to treat patients with ULT once the decision to do so has been reached. Education of patients is vitally important, as many patients stop therapy when they get another attack as they believe their medication to be ‘no longer working’. Some 20-30 per cent of patients will experience further attacks in the first six-to-12 months of initiation of ULT, after which if they are at target and adhere to therapy, events are very rare.

Finally, hyperuricaemia is associated with a higher incidence of cardiovascular events in population studies and portends a worse prognosis in women with eclampsia and HELLP syndrome. Of further interest, several studies have shown that gout patients treated with allopurinol who adhere to their therapy reduce their subsequent risk of cardiovascular events compared to those who were not treated.

Investigators are actively studying whether hyperuricaemia has a direct link with atherosclerosis and vascular inflammation. Rare hypersensitivity reactions have been reported with ULT. Physicians should make themselves aware of the PIL prior to prescribing any medication. Referral to a rheumatologist is always welcome and should be sought if there are doubts about the diagnosis or treatment, or concerns about the management strategy.

  1. on October 4, 2019 at 11:03 am

    concise and informative

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